ORIGINAL ARTICLE

GC Raangs
EG Winkel
AJ van Winkelhoff

Authors afliations:
GC Raangs, AJ van Winkelhoff, University of
Groningen, Department of Medical
Microbiology, University Medical Center
Groningen, Groningen, The Netherlands
EG Winkel, AJ van Winkelhoff, University of
Groningen, Center for Dentistry and Oral
Hygiene, University Medical Center
Groningen, Groningen, The Netherlands
Correspondence to:
Prof. Dr AJ van Winkelhoff
Antonius Deusinglaan 1
9713 AV Groningen
The Netherlands
Tel.: +31 50 636 2995
Fax: +31 50 636 2696
E-mail: a.j.van.winkelhoff@umcg.nl

In vitro antimicrobial effects of two

antihalitosis mouth rinses on oral
pathogens and human tongue
microbiota
Abstract: Objectives: The aim of the study was to compare the
antimicrobial activity of a mouth rinse containing chlorhexidine and
cetylpyridinium chloride (MR1) with a stannous fluoride-based mouth
rinse (MR2) in vitro. Materials and methods: Samples of the tongues
from 10 subjects with and 10 subjects without halitosis were
inoculated on blood agar plates. The agar was perforated, and the
cylindrical holes were filled either with mouth rinse MR1 or with mouth
rinse MR2. After incubation, inhibition zones of the whole tongue
microbiota and Fusobacterium nucleatum were measured. In addition,
MR1 and MR2 were applied in a short interval killing test (SIKT) on
four oral pathogens Porphyromonas gingivalis, Prevotella intermedia,
F. nucleatum and Aggregatibacter actinomycetemcomitans. Total
viable cell counts were made after two minutes of incubation with
increasing concentrations of MR1 and MR2. Results: MR1 showed a
significantly higher in vitro antimicrobial activity against the whole
tongue microbiota and F. nucleatum than MR2 in both groups of
subjects. In the SIK test, MR1 showed a significantly greater killing
capacity than MR2. The results show that a mouth rinse with low
concentrations of chlorhexidine and 0.05% cetylpyridinium chloride
appears to be more effective in inhibiting growth of the human tongue
microbiota in vitro than a fluoride/stannous fluoride-containing mouth
rinse. Conclusion: This in vitro observation supports the use of
chlorhexidine and cetylpyridinium chloride in the treatment of oral
halitosis.
Key words: bacteria; halitosis; in vitro; mouth rinses

Introduction
Dates:
Accepted 9 November 2012
To cite this article:
Int J Dent Hygiene
DOI: 10.1111/idh.12014
Raangs GC, Winkel EG, van Winkelhoff AJ.
In vitro antimicrobial effects of two antihalitosis
mouth rinses on oral pathogens and human tongue
microbiota.
2013 John Wiley & Sons A/S

Foul body odour, also known as kakidrosis (13), is a taboo in our society.
Conditions that are associated with body odours are bromidrosis (the
secretion of foul-smelling sweat), flatulence (excessive production of
bowel gases) (4, 5) and halitosis (bad breath) (6, 7). One factor these conditions have in common is the essential role of bacteria in the aetiology
of these conditions. Clinical surveys have shown that over 90% of all bad
breath odours originate in the oral cavity, and this condition is called oral
halitosis, bad breath or oral malodour (6, 8). If the origin of the source
resides outside the oral cavity, it is named extra-oral halitosis (9).
The cause of halitosis is multi-factorial, but bacteria present in a biofilm at the dorsum of the tongue play an important role in the development of this condition (10). Some of these bacteria produce malodorous
Int J Dent Hygiene |

Raangs et al. Antihalitosis mouth rinses

volatile sulphur compounds (VSC), products of metabolic

breakdown of the sulphur-containing amino acids methionine,
cystine and cysteine, which are formed from protein hydrolysis
of human tissues (11, 12). VSC are strongly associated with
halitosis (1315). McNamara et al. (13) observed that mainly
Gram-negative microorganisms were responsible for VSC formation and were therefore considered the cause of bad breath.
Yasukawa et al. (14) reported an increase in total VSC and
organoleptic scores in subjects with increased numbers of
Treponema denticola and F. nucleatum in tongue plaque, while
the presence of both species in subgingival plaque did not
show a gain of total VSC and organoleptic scores. Besides
causing malodour, VSC in the oral cavity may play a role in
periodontal disease (1619). Exposure of methyl mercaptan
and hydrogen sulphide to human gingival fibroblasts affects
the protein and collagen metabolism in human gingival tissue (20).
Treatment of oral halitosis is based on reduction of the
bacterial biofilm on the dorsum of the tongue. This is
achieved by the removal of plaque deposits mechanically
with toothbrush or tongue scraper and chemically by the use
of a mouth rinse. Both interventions have been shown to
reduce VSC levels in exhaled breath (12, 2123). Mouth
rinses containing zinc salts can act as a protective agent
through binding of zinc to mucosal tissues thereby inactivating VSC and maintaining the permeability barrier (24). Zinc
ions also directly bind volatile sulphur molecules and reduce
levels of VSC (22). Chlorhexidine and cetylpyridinium chloride (CPC) are chemical compounds that derive their antimicrobial and anti-VSC characteristics from their ability to
modify the hydrophobic regions of the bacterial cell walls
(25). The effect of CPC is relatively small compared to that
of chlorhexidine, but it is suitable for frequent and longer
use (26). Stannous fluoride has shown activity against a range
of oral microbes including streptococci as well as oral anaerobes (27). Although many mouth rinses are available, only a
few have been specifically designed to combat intra-oral halitosis. The clinical effectiveness of antihalitosis oral rinses is
based on antimicrobial activity and binding of VSC. Although
clinical studies have been carried out, the antimicrobial activity has often not been established. The aim of this study was
to study the antimicrobial activity of a chlorhexidine-containing (MR1) and a non-chlorhexidine-containing (MR2) mouth
rinse. Two in vitro models were used to test the antimicrobial
activity of the two mouth rinses: (i) by determining the
growth inhibition of the whole human tongue microbiota and
F. nucleatum, and (ii) by determining the short interval killing
capacity of both mouth rinses on planktonic monocultures of
four oral pathogens.

Materials and methods

Study population and methodology

The ethical committee responsible for clinical studies conducted by the University Medical Center Groningen approved
the study protocol.
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| Int J Dent Hygiene

Twenty subjects were recruited for this study: 10 subjects

without and 10 subjects diagnosed with intra-oral halitosis.
The subjects with intra-oral halitosis were recruited from
patients visiting a dental practice and had an organoleptic
score  3 on a scale of 05 (22). The subjects without halitosis
were volunteers from the dental department of the University
Medical Center Groningen with an organoleptic score  1.
None of the subjects suffered from severe or advanced
periodontitis, but some showed moderate gingivitis.
Sampling and culturing

From each subject, a sample from the biofilm on the dorsum of the tongue was obtained by zigzag streaking with a
sterile swab from the dorsal to the ventral site of the tongue
while rotating the swab. The samples were transferred to
vials containing 1.5 ml reduced transport fluid (28) and vortexed twice for 1 min with an interval of five minutes. After
homogenization, tenfold dilution series were prepared in
sterile saline, and aliquots of 100 ll of 10 3, 10 4 and 10 5
dilutions were transferred to 5% sheep blood agar plates
(Oxoid no. 2; Oxoid, Basingstoke, UK) supplemented with
5 mg l 1 hemin, 1 mg l 1 menadione) and spread using a
sterile Drigalski loop to obtain homogeneous growth. After
inoculation, four holes (diameter 7 mm) were punched in
the agar plates and filled with either 60 ll of MR1 (in
duplicate) (Halita; Dentaid, Cerdanyola, Spain) or MR2 (in
duplicate) (Meridol; Gaba, Weesp, The Netherlands). The
chemical compositions of the 2 rinses are summarized in
Table 1.
60 ll of sterile saline (0.9% NaCl in water) was used as negative control and was tested in separate plates. Processing of
the samples was performed in air. All experiments were performed in duplicate. Plates were incubated in jars in an atmosphere of 80% N2, 10 H2 and 10% CO2 at 37C for up to
5 days (Anoxomat; Mart Microbiology, Drachten, The Netherlands). Inhibition zones were measured after 3 and 5 days of
incubation.

Table 1. Chemical composition of the two mouth rinses used in

this study
MR1

MR2

Chlorhexidine digluconate 0.05%

Cetylpyridinium chloride 0.05%
Zinc Lactate 0.14%
Aqua
Glycerin
Propylene glycol
Xylitol
Digluconate
PEG-40 Hydrogenated castor oil
Gluconic acid
Sodium saccharin
Aroma
Cl 42090

Hydrochloric acid
Aqua
Zinc lactate
Olaflur
Propylene glycol
Xylitol
Stannous fluoride 125 ppm
Amine fluoride 125 ppm
Hydrogenated castor oil
PEG 40
Odium saccharin
Aroma
Cl 42051

Raangs et al. Antihalitosis mouth rinses

Microbial inhibition zones

After 3 days of incubation, plates with semi-confluent growth

were selected, and the diameter of the antimicrobial inhibition
zones of the whole tongue microbiota was measured at three
different positions at each of the two wells of MR1 and MR2.
An average value was calculated from the six measurements of
the two MR1 and the two MR2 zones.
Inhibition of monocultures of periodontal pathogens

To determine the antimicrobial activity of the two mouth

rinses after a short exposure time, the short interval killing test
(SIKT) was applied (29). Three strict anaerobic bacterial species P. gingivalis (Pg, ATCC 33277), P. intermedia (Pi, ATCC
25611) and F. nucleatum (Fn, ATCC 10953) and the capnophilic species A. actinomycetemcomitans (Aa, ATCC 33384) were cultured in brain heart infusion broth (BHI-2). The cultures were
harvested at exponential growth and mixed to a total volume
of 5 ml with increasing amounts of MR1 or MR2 ranging from
10%, 20%, 40% and 60% (v/v). The mixtures of mouth rinse
and bacterial cells were incubated at 37C by constant rotation. After incubation for 2 min, tenfold dilution series were
prepared, and aliquots of 100 ll of the 10 5, 10 6 and 10 7
dilutions were seeded on blood agar plates to determine total
viable cell counts. Dilution series of cultures without mouth
rinse were prepared, seeded and used as controls. Anaerobic
incubation of the plates was performed as described. The survival of the bacteria after exposure to the MR1 and the MR2
mouth rinses was calculated as proportions of the control and
expressed in percentages of survival. The experiments were
performed five times in independent tests.
Data analysis

Data are expressed as mean (standard deviation, SD). The students t-test (unpaired, two-tailed) was applied for assessing
differences in the mean inhibition zones and the MannWhitney U-test (independent samples, two-tailed) for differences in
inhibition of monocultures of periodontal pathogens between
the two mouth rinses. P < 0.05 was regarded as significant.

Results
The negative controls with sterile saline produced no inhibition of the whole tongue microflora in any of the experiments.
Mean inhibition zones of the two rinses on whole tongue microbiota from the 10 subjects with and 10 subjects without oral
halitosis are shown in Table 2.
No differences between the mean inhibition zones after 3
and 5 days of incubation were observed. The growth inhibition
zones of MR1 or MR2 on the whole tongue microbiota of the
non-halitosis subjects did not differ from those of the halitosis
subjects. MR1 showed a significantly higher in vitro antimicrobial activity against the whole tongue microbiota of both halitosis (P < 0.0001) and non-halitosis subjects (P < 0.0001) in

Table 2. Mean inhibition zones (mm) and standard deviations

(SD) of 2 oral mouth rinses on whole tongue microbiota and
F. nucleatum from the 10 subjects with and 10 subjects without
halitosis

Inhibition zone of
whole tongue
microbiota (mm)
Inhibition zone of
F. nucleatum (mm)

Non-Halitosis

Halitosis

MR1

MR2

MR1

MR2

17 (0.9)*

11 (0.8)

16 (1.2)*

11 (0.6)

9 (2.2)

6 (1.2)

9 (1.6)

6 (0.7)

*Significantly greater inhibition zone of MR1 than MR2, P < 0.0001.

Significantly greater inhibition zone of MR1 than MR2, P < 0.0014.

comparison with MR2. Because a clear specific inhibition of

F. nucleatum was observed, it was possible to measure the distance from the centre of the punch hole to the nearest F. nucleatum colonies. The specific mean inhibition zones of F. nucleatum
were significantly greater by MR1 than by MR2 in both halitosis
(P = 0.0014) and non-halitosis subjects (P < 0.0001) (Table 2).
The results of the SIKT test are shown in Figures 1ad.
Both mouth rinses showed a concentration-dependent antimicrobial activity. There were marked differences in the susceptibility of the tested species towards the two mouth rinses.
P. gingivalis (Fig. 1a) was most susceptible to MR1; a significantly better killing was observed by MR1 at all concentrations tested (P < 0.05). At a concentration of 10% (v/v), 3%
survival was observed for MR1 and 54% for MR2. No differences in survival were found for P. intermedia (Fig. 1b).
Besides for P. gingivalis, differences between MR1 and MR2
were also observed for F. nucleatum (Fig. 1c) and A. actinomycetemcomitans (Fig. 1d). While almost complete killing was
obtained with 40% MR1, MR2 showed significantly (P < 0.05)
less killing effects on these two species with still some bacterial survival at 60%.

Discussion
In this study, the antimicrobial activity of two mouth rinses
commonly used to treat oral halitosis was investigated in vitro.
Two models were used to study the ability to affect the
growth of whole tongue biofilm bacteria and monospecies cultures of oral pathogens. The rational for this study is based on
the concept that oral halitosis has a bacterial aetiology. The
rationale for the selected two mouth rinses was the fact that
both products have been designed to combat intra-oral halitosis and claim antimicrobial activity. To test the antimicrobial
effects of both mouth rinses, the growth inhibition capacity on
whole tongue microbiota and the differential inhibition capacity of F. nucleatum sp. were tested. In addition, the short interval killing characteristics of both mouth rinses were studied
using planktonic monocultures of four oral pathogens. The
observation of similar growth inhibition zones of the tongue
biofilm bacteria from subjects with and without halitosis can
be explained by the non-specific antimicrobial effects of
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Raangs et al. Antihalitosis mouth rinses

(b)

70

MR1

35

MR1

60

MR2

30

MR2

Survival (%)

Survival (%)

(a)

50
40
30
20

20
15
10
5

10
0

25

10

20

40

60

Percentage mouth rinse of total volume

(d)
MR1
MR2

Survival (%)

Survival (%)

(c)

100
90
80
70
60
50
40
30
20
10
0

10

20

40

10

20

40

60

Percentage mouth rinse of total volume

60

Percentage mouth rinse of total volume

80
70
60
50
40
30
20
10
0

MR1
MR2

10

20

40

60

Percentage mouth rinse of total volume

Fig. 1. In this short interval killing test (SIKT), an increasing volume (v/v) of antimicrobial agent is added to a bacterial suspension in BHI broth.
After 2 minutes of exposure, the percentage of surviving bacterial cells relative to the initial inoculum was determined. On the x-axis, the percentage (v/v) of mouth rinse relative to the total volume is depicted. (a) P. gingivalis. Growth inhibition of MR1 is significantly greater at all concentrations (P < 0.01). (b) P. intermedia. Growth inhibition of MR1 and growth inhibition MR2 are not significantly different (P > 0.05). (c) F. nucleatum
Growth inhibition of MR1 is significantly greater at 20%, 40% and 60% concentrations (P < 0.01). (d) A. actinomycetemcomitans. Growth inhibition of
MR1 is significantly greater at all concentrations (P < 0.01).

chlorhexidine and CPC in MR1 and of amine fluoride/stannous

fluoride in MR2. In both experiments, MR1 showed a significantly higher antimicrobial effect than MR2. The strong effect
of MR1 on F. nucleatum is also noteworthy. This species has
been implicated in the aetiology of intra-oral halitosis by several
authors (14, 30, 31), and this observation can explain the effect
of MR1 on organoleptic and objective halitosis scores (22, 32).
The greater antimicrobial effect of MR1 was also apparent
in the short interval killing experiment. In this experiment,
the killing potential of an antimicrobial agent is tested after a
contact time of only 2 min. This information may be relevant
because rinsing or gargling is usually performed for a short
time. At low concentration, MR1 showed a significant killing
effect on P. gingivalis, a species that is a strong producer of
VSC (33, 34) and frequently detected on the dorsum of the
tongue in oral halitosis patients (35). MR1 showed stronger
killing effects in comparison with MR2 for three of the four
pathogens tested. Antihalitosis rinses have multiple actions to
reduce oral bad breath. Capturing the produced VSC by zinc
lactate is one mode of action, and reducing the VSC-producing
bacterial load on the tongue dorsum is a second mode of
action. Only the antimicrobial capacity of both mouth washes
was tested in this study. MR1 is one of few products that have
been tested for its antihalitosis activity in a double-blind, placebo-controlled study in patients with overt oral halitosis, and
has shown clinical efficacy (22). Treatment with MR1 has
demonstrated reduction in VSC values and scored high on sensory tests in a comparative study (36). Furthermore, MR1 has
recently been used as a reference in a study with MR2 (37).
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| Int J Dent Hygiene

Conclusions
On the basis of the observation made in this in vitro study, we
conclude that an oral mouth rinse containing a low concentration of chlorhexidine and 0.05% CPC is more effective than
an oral mouth rinse containing fluoride/stannous fluoride, in
inhibiting tongue microbiota in vitro of both healthy subjects
and patients with oral halitosis. Also, short contact time of a
chlorhexidine-containing mouth rinse results in killing of oral
Gram-negative VSC-producing anaerobes.

Acknowledgements
The study was funded by the Department of Dentistry and
Oral Hygiene, University Medical Center Groningen, University of Groningen.

Conflict of interest
The authors declare that they have no conflict of interests.

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